It is well known that many compounds of general formula (I) having a phenylacetic acid skeleton present biological activity as antiinflammatory and antirheumatic agents. Besides the antiinflammatory effect most of the compounds in this class have also analgesic and antipyretic activities. Some examples of such substances are diclofenac, flurbiprofen and ibuprofen (Roth, H. J. and Kleemann, A., "Pharmaceutical Chemistry", Vol. 1, Pp. 92-93, John Wiley and Sons, Chichester, 1988). ##STR2##
U.S. Pat. No. 5,220,064 describes substituted 4'-hydroxy phenylacetic acid and phenylacetamide derivatives having antiinflammatory and analgesic activities. Among the compounds included in the definition of formula I of the patent there are the following: ##STR3## wherein R.sub.2 could be hydrogen or lower alkyl, B could be ##STR4## but X must be hydrogen or lower alkyl, i.e. X can not be halogen. Moreover, X is never a gem-difluoro group. Also the aromatic ring always has hydroxyl group at para position.
FR 2,499,981 describes a synthesis of phenylacetic acid derivative obtained by basic hydrolysis of 7-benzoyl-methylindol-2-one with general formula as followed: ##STR5## Wherein R.sub.1 is always methyl and X is hydrogen, never a gem-difluoro group.
Important differences in biological activity may commonly be expected based on the difference in eletronegativity between fluorine and hydrogen as well as the higher C--F bond strength versus the strength of the C--H bond. In addition, as a consequence of the electron density, fluorine can function as hydrogen bond acceptor at the active site (Libman, J. F; Greenberg, A. and Dolbier Jr., W. R. "Fluorine Contain Molecules", VCH Publishers, New York, 1988). Indeed, a great variety of biologically active compounds having the so-called gem-difluoro function (CF.sub.2), such as sugars, nucleic acids, prostaglandins, steroids, are known and have been described in: (i) Welch, J. T. Tetrahedron, 1987, 43, 3123; (ii) Welch, J. T. and Eswarakrishan, S., "Fluorine in Bioorganic Chemistry", J. Wiley & Sons., N. York, 1991. (iii) Borthwick, A. D. et al, J. Med. Chem., 1990, 33, 179; (iv) Kornov, A. M. et al, Tetrahedron: Asymmetry, 1995, 6, 199.
Some .alpha.,.alpha.-difluorophenylacetic acids and .alpha.,.alpha.-difluorophenylacetamide derivatives were prepared by the selective replacement of the .alpha.-oxo group from .alpha.-oxoarylacetates using DAST (diethylamino sulfur trifluoride) as fluorinating reagent (Middleton, W. J. and Bingham, E. M., J. Org. Chem., 1980, 45, 2883-2887). According to Middleton and Bingham, it could be expected some change on the biological activity when two fluorine atoms are introduced in .alpha.,.alpha.-difluoroarylacetic acid compounds. However, the type and/or intensity of the possible modifications are unpredictable as demonstrated by the examples presented. The difluoro analogue (.alpha.,.alpha.-difluoro-4-isobutyl-phenylacetic acid) of the synthetic antiinflammatory drug ibufenac (4-isobutyl-phenylacetic acid) prepared by the authors was essentially inactive as an antiinflammatory agent, while the difluoro analogue (.alpha.,.alpha.-difluoro-.alpha.-naphthylacetic acid) of the plant-growth regulate (.alpha.-naphthylacetic acid) had a comparable biological activity.
Isatins (indol-2,3-diones) of general formula (II) are versatile starting materials for a variety of other important classes of heterocyclic compounds. They can be easily prepared from inexpensive and available anilines (Holt, J. S. et al, J. Chem. Soc., 1958, 1217; Huntress, E. H. et al, J. Am. Chem. Soc., 1949, 71, 745; Maginnity, P. M. et al, J. Am. Chem. Soc., 1951, 73, 3579). Isatins have two different carbonyl groups, the C-3 carbonyl having a strong ketonic character and, thus suitable to react selectively with DAST (diethylamino sulfur trifluoride), a specific reagent for nucleophilic addition to ketone and aldehyde carbonyls, to give gem-difluoroindoles. ##STR6##
To overcome the difficulties in producing synthetic antiinflammatory and antirheumatic agents with high yields and high biological activities, the present invention provides a process to synthesise novel gem-difluoro derivatives of phenylacetic acid and phenylacetamide from of the fluorination of isatins with DAST and subsequently reaction with alcohols, thiols, water, hydroxides solutions and amines, with concomitant opening of heterocyclic ring.